1. Field of the Invention
The present invention relates generally to a method for improving memory in mammals including humans by administering to the mammal a composition including at least one melatonin receptor antagonist, where the composition reverses inhibitory effects of melatonin in the mammal.
More particularly, the present invention relates a method for improving memory in healthy mammals including humans by administering to the mammal a composition including at least one melatonin receptor antagonist, where the composition reverses inhibitory effects of melatonin in the mammal permitting enhanced learning and/or post learning performance of cognitive learning activities such as studying, task oriented training, or the performance of any other task or skill that has a cognitive memory component thereto.
2. Description of the Related Art
A variety of over-the-counter substances are said to improve memory, including herbs and supplements, with little evidence of efficacy and little understanding of their mechanism of action. In addition to these supplements, some drugs have been developed to remediate deficiencies of the central nervous system, such as modafinil, methylphenidate, and dextroamphetamine. Some of these drugs are known to be occasionally used to improve the cognitive performance of healthy subjects, such as the use of dextroamphetamine among the military. These three above mentioned drugs are all stimulants that act by affecting norepinephrine and dopamine levels. The present invention however makes use of melatonin receptor antagonists as a method for improving memory in healthy subjects—defined as subjects that do not show signs of central nervous system disorders.
In mammals, melatonin has been implicated in the transduction of photoperiodic information, modulation of a variety of neuronal and endocrine functions, regulation of reproduction, metabolism, sleep, retina physiology, cardiovascular and immune functions, cancer cell growth and the control of circadian rhythms. Some studies have clarified the production of melatonin. Melatonin (5-OCH3 N-acetyltryptamine) is the principal hormone produced by the pineal gland. The circadian oscillator of both the pineal gland and retina in most organisms studied to date have been shown to regulate melatonin synthesis, with increased melatonin production during the night and reduced melatonin synthesis during the day. For diurnal organisms such as humans and zebrafish, the period of increased melatonin production coincides with the organism's habitual hours of sleep and the onset of melatonin secretion correlates with the onset of evening sleepiness. The effects of melatonin, at least in part, are mediated through high affinity G protein-coupled melatonin receptors.
Membrane bound melatonin receptors are classified according to pharmacological and kinetic properties into two classes (ML1 and ML2). Three receptors with ML1 pharmacological characteristics have been cloned in several vertebrate species including humans (Mel1a Mel1b, Mel1c). Mammalian melatonin receptors are now known as MT1 for Mel1a and MT2 for Mel2b. Both MT1 and MT2 share 60% amino acid homology.
Luzindole (or N-Acetyl-2-benzyltryptamine) is one of several melatonin receptor antagonists. It is known to be a competitive melatonin antagonist that is effective in blocking melatonin receptors in brain and is active in vivo. Behavioral tests in C3H/HeN mice show that treatment with luzindole decreases the duration of immobility during swimming with a more pronounced effect at midnight, when endogenous melatonin levels are elevated as compared to midday time. Further studies suggest that luzindole may exert like an antidepressant by blocking endogenous melatonin mediated signaling in the central nervous system.
K-185 (or N-butanoyl-2-(5,6,7-trihydro-11-methoxy-benzo[3,4]cyclohept[2,1-a]indol-13-yl) ethanamine) is yet another type of melatonin receptor antagonist with over a 140-fold higher affinity for MT2 than for MT1 subtypes of melatonin receptors. However, the affinity kinetics and binding characteristics of K-185 and other melatonin receptors differ among animal types. K-185 has antagonizing effects to melatonin in some animal models, while K-185 shows partial agonistic characteristics in other animal models. Studies in zebrafish embryos reveal that K-185 has antagonistic properties by blocking the effect of melatonin on zebrafish development.
Prior to the development of melatonin receptor antagonists and even today, conventional methods for purposely regulating melatonin levels include (1) the use of an external bright light treatment, or (2) the removal of the pineal gland. Removal of the pineal gland may not significantly lower endogenous melatonin levels, as other melatonin producing sites such as the retina and digestive system exist and they may substantially contribute to modulating melatonin levels. However, with the availability of a competitive melatonin receptor antagonist such as luzindole, the classical methods in antagonizing endogenous melatonin levels such as bright light and pinealectomy can be mimicked. The advantage of using competitive melatonin receptors over conventional techniques is two fold: (1) it avoids the need for surgical interventions, such as pinealectomy, and (2) it probably has less effect on the circadian system than bright light does. Luzindole and other melatonin receptor antagonists have been used mainly in in vitro studies involving the localization or distribution and characterization of melatonin receptors in various tissues. However, to date no study has addressed the behavioral impact of melatonin receptor antagonists.
It is therefore the purpose of this invention to take advantage of the effect of melatonin receptor antagonists, including but not limited to luzindole and/or K-185, particularly with regards to improving memory in healthy subjects.